Repurposing therapy of ibrexafungerp vulvovaginal candidiasis drugs as cancer therapeutics

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Mechanism ibrexafungerp for anticancer
Ibrexafungerp has antifungal activity by inhibiting (1,3)-β-Dglucan synthase (Apgar et al., 2021).This mechanism gives Ibrexafungerp a good toxicity profile in host cells.The pharmacokinetic profile of Ibrexafungerp is well-classified, with the ability to penetrate tissues and organs, such as the liver, lungs, and skin.This pharmacokinetic profile is influenced by the structure of Ibrexafungerp, which has a core phenanthropyran Frontiers in Pharmacology frontiersin.org02 carboxylic acid ring system at position 15 and 2-amino-2,3,3trimethyl-butyl ether at position 14, both of which are derivatives of the naturally occurring hemiacetal triterpene glycoside enfumafungin.The pharmacokinetic profile in animals shows that Ibrexafungerp has a 30%-50% bioavailability when administered orally and has poor penetration into the central nervous system.In vitro studies show hydroxylation metabolism by the CYP3A4 isoenzyme with primary excretion via bile.The steady-state volume of distribution (Vss) profile in humans averages 600 L with high binding to protein, mainly albumin (Apgar et al., 2021;Angulo et al., 2022).
The potential of Ibrexafungerp as a cancer therapeutics is based on the use of antifungals, which have been used as anticancer agents.Antifungals with anticancer activity include itraconazole, rapamycin, griseofulvin, clotrimazole, ciclopirox, and nannocystin A (Li et al., 2022;Mohi-ud-din et al., 2023).The mechanisms of antifungal drugs that act as anticancers include the function of increasing autophagy, reducing angiogenesis, increasing tumor regression, and reducing metastasis (Mohi-ud-din et al., 2023).
The mechanism of ibrexafungerp has the same action as micafungin, which is one of the echinocandin classes of antifungal agents.The mechanisms of action of Ibrexafungerp and micafungin as antifungals may have mechanisms similar to anticancer.The predicted mechanism of ibrexafungerp is to inhibit the neddylation process by stabilizing ubiquitin-conjugating enzyme 2 M (UBE2M).This enzyme is essential in molecular mechanisms such as DNA damage, apoptosis, and cell proliferation (Mamun et al., 2023a).The prediction of the Ibrexafungerp mechanism can be seen in Figure 1A (Mamun et al., 2023b;Mamun et al., 2023a;Yu et al., 2020b;Zheng et al., 2021;Zhou et al., 2023).
Prediction of the mechanism of ibrexafungerp as a UBE2M inhibitor can inhibit the neddylation pathway which can reduce tumor-promoting factors and increase levels of tumor suppressors thereby improving the occurrence of tumors and prognosis (Zheng et al., 2021).Anticancers that target UBE2M in the neddylation

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process play a role in posttranslational modification mechanisms and target protein activity.The neddylation process begins with NEDD8 which is activated by E1 NEDD8-activating enzyme (NAEconsists of NAE1 and UBA3).This activation process results in the formation of the thioester-linked E1-NEDD8 complex which is then transferred to the NEDD8-conjugating enzyme (E2)/UBE2M (Yu et al., 2020b;Zheng et al., 2021).Ibrexafungerp inhibits the NEDD8 mechanism in UBE2M so that it cannot proceed to the next stage, namely, transferring NEDD8 from charged E2 to lysine residues in its target (Zhou et al., 2023).
Ibrexafungerp has a structure that belongs to the triterpenoid class (Angulo et al., 2022;Kumar et al., 2024).The triterpenoid group has the potential to be a cancer chemotherapy agent with a mechanism as a reactive oxygen species (ROS) modulator that can regulate cell survival and function.The impact of ROS on cancer cells is the mechanism of autophagy and ferroptosis (Endale et al., 2023;Jiang et al., 2021;Lee et al., 2023;Ling et al., 2022;Zeng et al., 2023).Autophagy works by causing cellular lipid accumulation and, ultimately, cell death.Another mechanism is inducing ferroptosis, which can cause increased chemosensitivity to chemotherapy drugs that are used to treat cancer cells.The mechanism of ibrexafungerp as a ROS modulator can be seen in Figure 1B (Ling et al., 2022).

Computational approaches ibrexafungerp
The development of ibrexafungerp as a cancer therapeutic can be done through 2 methods: experimental screening and computational (virtual) screening (Oliveira et al., 2023;Prada Gori et al., 2023;Weth et al., 2024).Experimental screening involves in vivo and in vitro research with drug-based phenotypic screens and target-based high throughput assays.Computational (virtual) screening methods include signature matching (-omics data), artificial intelligence (machine learning and deep learning), GWAS disease/target associations, and chemical similarity and molecular docking (Weth et al., 2024).A virtual screening server that can be used in computational approaches in the development of drug repurposing research, namely, DrugRep.The use of DrugRep in drug repurposing research uses receptor-based and ligand-based screening systems (Gan et al., 2023).Several tools can be used to develop anticancer from Ibrexafungerp, some of which can be seen in Table 1.

Conclusion
Ibrexafungerp is predicted to have two anticancer mechanisms.The anticancer mechanism is obtained by inhibiting the neddylation stage by stabilizing UBE2M, and Ibrexafungerp acts as a ROS modulator, which acts through cell death mechanisms with autophagy and ferroptosis.

FIGURE 1 (
FIGURE 1 (A) Mechanism of Ibrexafungerp in inhibiting the neddylation process and (B) Mechanism of Ibrexafungerp as a ROS modulator.

TABLE 1
Computational tools in cancer research.